Controlled release of miotic and mydriatic drugs in the anterior chamber

ABSTRACT

The present invention relates to compositions which maintain the structural integrity of the anterior chamber of the eye during ophthalmologic surgery, thereby protecting the tissues that form and line the anterior segment from potential damage and simultaneously providing sustained delivery of a miotic or mydriatic agent. The present invention provides for compositions which comprise a viscoelastic polymer, wherein sustained release of a miotic or mydriatic agent is mediated by ionic interactions, as well as for compositions wherein sustained release of a miotic or mydriatic agent is mediated by microcapsules or copolymer micelles.

INTRODUCTION

The present invention relates to compositions, comprising a viscoelasticpolymer and a miotic or mydriatic agent, which maintain the structuralintegrity of the anterior chamber of the eye during ophthalmologicalsurgery, thereby protecting the tissues that form and line the anteriorsegment from potential damage and simultaneously providing sustaineddelivery of a miotic or mydriatic agent. The present invention alsoprovides for compositions wherein sustained release of a miotic ormydriatic agent is mediated by microcapsules or copolymer micelles.

BACKGROUND OF THE INVENTION

Maintaining the integrity of the anatomic components of the eyefacilitates the delicate manipulations, performed within small areas, ofophthalmological surgery.

One component which may be controlled is the anterior chamber of theeye. As shown in FIG. 1, the anterior chamber is located between thecornea and the iris. Just posterior to the iris is the lens, which isinterposed between the anterior chamber and the larger vitreous chamber,filled with vitreous humor. Maintaining the structural integrity of theanterior chamber minimizes the risk that the endothelium and/or the iriswill be damaged during surgery. The introduction of viscoelasticmaterials, such as sodium hyaluronate, chondroitin sulfate,hydroxypropyl methylcellulose, and methylcellulose, into the anteriorchamber prevents the chamber from collapsing during surgery.

Another component that may be controlled is pupil size. During cataractsurgery, it is desirable that the pupil is dilated, so that access tothe lens is simplified and the insertion of a posterior chamber implantis facilitated. A variety of mydriatic drugs, such as atropine (acholinergic blocker), phenylephrine (an adrenergic stimulator), andprostaglandin inhibitors have been used in this regard, and havehitherto predominantly been administered via external application.

Conversely, in refractive implants and secondary aphakic implants, asmaller ("miotic") pupil is desirable, in order to reduce iris trauma,avoid anterior synechias, prevent iris tucking, and facilitateappropriate positioning of the implant. Externally applied pilocarpineand carbachol (cholinergic stimulators), and physostigmine, demecariumbromide, echothiophate iodide, and isofluorphate (cholinesteraseinhibitors) have been used for this purpose.

During surgery, however, and in the open eye, the efficacy of topicalmedication is reduced. Dilution and runoff preclude a continued highdose of effective medication. Even the direct introduction of mioticagents such as acetylcholine chloride or carbachol do not provide longterm effects and often require frequent repeated administration into theopen eye.

Previous attempts to achieve long-term maintenance of effective druglevels have employed sustained drug delivery technology, using systemicor transdermal administration, or the positioning of a bioerodible drugdelivery device external to the eye. Such methods have been usedprimarily to control intraocular pressure in glaucoma patients. However,prior to the present invention, no method has been devised whichcombines sustained mydriatic or miotic drug delivery with maintenance ofthe structural integrity of the anterior chamber.

SUMMARY OF THE INVENTION

The present invention relates to compositions which may be used tomaintain the structural integrity of the anterior chamber of the eye andto provide sustained release of a-miotic or mydriatic agent. In variousembodiments of the invention, compositions of the invention comprise aviscoelastic polymer, wherein sustained release of a miotic or mydriaticagent is mediated by ionic interactions. In further embodiments of theinvention, sustained release of a miotic or mydriatic agent is mediatedby microcapsules or copolymer micelles. In particular embodiments, thecompositions of the invention may be used to provide both rapid releaseof miotic or mydriatic agent as well as slower, sustained release.

DESCRIPTION OF THE FIGURE

FIG. 1. Clemente, 1978, in "Anatomy", Lea and Fibiger, Philadelphia,FIG. 501.

FIG. 2. Dilution effect of miotic or mydriatic agents in the anteriorchamber of the eye caused by the normal turnover rate of aqueous humor,in the presence or absence of viscoelastic polymer-drug complex. Curve Arepresents unbound drug=0.0500 moles/liter in physiological saline;Curve B represents unbound drug=0.025 moles/liter plus viscoelasticpolymer-drug complex=0.0500 equivalents/liter in physiological saline;and Curve C represents viscoelastic polymer-drug complex=0.100equivalents/liter in physiological saline.

DETAILED DESCRIPTION OF THE INVENTION

For clarity of presentation, and not by way of limitation, the detaileddescription of the invention is divided into the following sections:

(1) viscoelastic polymers;

(2) miotic agents;

(3) mydriatic agents;

(4) compositions of the invention; and

(5) methods for using the compositions of the invention.

VISCOELASTIC POLYMERS

The present invention provides for compositions comprising viscoelasticpolymers, including but not limited to the anionic viscoelastic polymershyaluronic acid (hyaluronate), chondroitin sulfate, dermatan sulfate,carboxymethylcellulose, heparin sulfate, keratan sulfate,carboxymethylhydroxypropylcellulose, carboxymethylhydroxethylcellulose,cellulose sulfate, cellulose phosphate, carboxymethylguar,carboxymethylhydroxypropylguar, carboxymethylhydroxyethylguar, xanthangum, carrageenan, anionic polysaccharides, anionic proteins andpolypeptides, anionic polyacrylamide, anionic poly-N-vinylpyrrollidone,anionic polydimethyl acrylamide, polymers and copolymers of2-acrylamido-2-methyl-propanesulfonic acid, acrylic acid and methacrylicacid. The foregoing compounds, in their nonionized forms, may functionas acidic polymers; in their ionized forms, the compounds may functionas polymeric anions.

The viscoelastic polymers of the invention range in molecular weightfrom 50,000 to 8,000,000 daltons, depending on the polymer of choice.For example, an average molecular weight of from 1,000,000 to 5,000,000daltons is commonly used for sodium hyaluronate, whereas an averagemolecular weight of greater than 80,000 daltons is normally used forhydroxypropylmethylcellulose. The concentration of viscoelastic polymermay vary from 1 mg/ml to 60 mg/ml, and preferably from 5 mg/ml to 30mg/ml. The viscosity of the viscoelastic polymer may vary from 1000centistokes to 60,000 centistokes, and preferably from 2,500 centistokesto 5,500 centistokes for hydroxypropylmethylcellulose and from 20,000centistokes to 40,000 centistokes for sodium hyaluronate. Suchviscosities not only enable the introduction of the polymer into the eyeby injection or extrusion, but also are viscous enough to remain withinthe anterior chamber (that is to say, will not run off easily), maintainits structural integrity, and permit easy withdrawal. Furthermore, theviscoelastic polymers of the invention are water soluble and can beeluted with time.

MIOTIC AGENTS

The present invention provides for compositions comprising miotic agentsincluding, but not limited to, pilocarpine, isopilocarpine, pilocarpinehydrochloride, pilocarpine nitrate, isopilocarpine hydrochloride,isopilocarpine nitrate, carbachol, physostigmine, physostigmine sulfate,physostigmine sulfite, demecarium bromide, ecothiophate iodide andacetylcholine chloride. Preferred agents are members of the pilocarpineand isopilocarpine family of compounds.

The miotic agents of the invention may be utilized in either neutral orcharged, cationic form, depending on the nature of the sustained drugdelivery to be provided by the composition. Of the foregoing list,agents that are considered basic include: pilocarpine, isopilocarpine,and physostigmine; agents that are considered hydrophobic include:pilocarpine, isopilocarpine, and physostigmine; and agents that areconsidered cationic include demecarium bromide, ecothiophate iodide,pilocarpine hydrochloride, pilocarpine nitrate, isopilocarpinehydrochloride, isopilocarpine nitrate, carbachol, physostigmine sulfate,acetylcholine chloride and physostigmine sulfite.

MYDRIATIC AGENTS

The present invention provides for compositions comprising mydriaticagents including, but not limited to, atropine, atropine sulfate,atropine hydrochloride, atropine methylbromide, atropine methylnitrate,atropine hyperduric, atropine N-oxide, phenylephrine, phenylephrinehydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide,hydroxyamphetamine hydrochloride, hydroxyamphetamine iodide,cyclopentolate, cyclopentolate hydrochloride, homatropine, homatropinehydrobromide, homatropine hydrochloride, homatropine methylbromide,scopolamine, scopolamine hydrobromide, scopolamine hydrochloride,scopolamine methylbromide, scopolamine methylnitrate, scopolamineN-oxide, tropicamide, tropicamide hydrobromide, and tropicamidehydrochloride. Preferred agents are members of the atropine family andphenylephrine family of compounds.

The mydriatic agents of the invention may be utilized in either neutralor charged, cationic form, depending on the nature of the sustained drugdelivery to be provided by the composition. Of the foregoing list,agents that are considered basic include: atropine, phenylephrine,hydroxyamphetamine, cyclopentolate, homatropine, scopolamine, andtropicamide; agents that are hydrophobic include atropine,phenylephrine, hydroxyamphetamine, cyclopentolate, homatropine,scopolamine, and tropicamide; and agents that are considered cationicinclude atropine sulfate, atropine hydrochloride, atropinemethylbromide, atropine methylnitrate, atropine hyperduric, atropineN-oxide, phenylephrine hydrochloride, hydroxyamphetamine iodide,hydroxyamphetamine iodide, hydroxyamphetamine hydrobromide,cyclopentolate hydrochloride, homatropine hydrobromide, homatropinehydrochloride, homatropine methylbromide, scopolamine hydrobromide,scopolamine hydrochloride, scopolamine methylbromide, scopolaminemethylnitrate, scopolamine N-oxide, tropicamide, and tropicamidehydrobromide.

COMPOSITIONS OF THE INVENTION

The present invention provides for compositions which provide sustainedrelease of miotic or mydriatic agents, as described above, in whichrelease of the agent is mediated by (1) ionic (including acid-base)interactions; (2) microcapsules; or (3) copolymer micelles. Thecompositions also provide a means for maintaining the structuralintegrity of the anterior chamber of the eye.

In a first set of nonlimiting embodiments, the present inventionprovides for compositions in which the sustained release of miotic ormydriatic agent is achieved through ionic interactions between the agentand a viscoelastic polymer. In particular embodiments, a composition maycomprise an anionic viscoelastic polymer and a cationic miotic ormydriatic agent, in which case the cationic agent of the composition,when placed in the eye, may be released by displacement with endogenoussodium or potassium ions, or other naturally occurring cations. In onespecific, nonlimiting embodiment, the anionic viscoelastic polymer acidmay be sodium hyaluronate, and the cationic agent may be the mydriaticagent atropine sulfate, where, in the preparation of the composition,sodium sulfate (and bisulfate) are removed by using an excess of theatropine sulfate in the presence of a lesser amount of sodiumhyaluronate followed by dialysis. This process may be repeated severaltimes to prepare a high purity of atropine hyaluronate. In anotherspecific, nonlimiting embodiment, the anionic viscoelastic polymer maybe chondroitin sulfate and the cationic agent may be the miotic agentpilocarpine, which may be combined by interacting sodium chondroitinsulfate with pilocarpine hydrochloride. In yet another specific,nonlimiting embodiment, an ion exchange interaction between sodiumhyaluronate and phenylephrine hydrochloride can be effected, yieldingphenylephrine hyaluronate.

In a second, related set of nonlimiting embodiments, the presentinvention provides for compositions in which the sustained release ofmiotic or mydriatic agent is achieved through ionic acid-baseinteractions between the agent and a viscoelastic polymer. In particularembodiments, a composition may comprise an acidic viscoelastic polymerand a basic miotic or mydriatic agent, in which case the composition,when placed in the approximately pH neutral environment of the eye, willprovide a relatively slow release of the miotic or mydriatic agent byionic displacement of the drug from existing cations. In one specific,nonlimiting embodiment, the acidic viscoelastic polymer acid may behyaluronic acid, and the basic agent may be the mydriatic agentatropine. When these two compounds are combined in the composition, thepolymeric salt atropine hyaluronate may be formed. In another specific,nonlimiting embodiment, hyaluronic acid may be interacted with the basicmiotic drug pilocarpine in water at a temperature range of 5 to 50° C.(wherein the pilocarpine becomes protonated by the polyacid and isrendered a salt of the viscoelastic polymer), followed by dialysis orultrafiltration to remove unreacted pilocarpine. The resultingpilocarpine hyaluronate composition may then, alternatively, either besterilized and adjusted to the appropriate pH and osmolality for use(for example, and not by way of limitation, where the pH range isbetween about 6.8 and 7.8, preferably between 7.2 and 7.4, and theosmolality is 285±55 mOsm/kg and preferably between 290 and 320mOsm/kg), or may be recovered by drying in vacuo or by lyophilization.In yet another specific, nonlimiting embodiment of the invention,hyaluronic acid may be interacted with the mydriatic agent phenylephrinein aqueous solution, using an excess of phenylephrine, followed bydialysis, yielding phenylephrine hyaluronate.

In a nonlimiting example relating to the sustained release of a mioticor mydriatic agent from the anterior chamber of the eye, FIG. 2 depictsthree representative conditions using an aqueous humor volume of 310microliters and an aqueous humor turnover rate of 1.5 microliters perminute (Schoenwald, 1993, "Pharmacokinetics in Ocular Drug Delivery"(Chapter 10) in Biopharmaceuticals of Ocular Drug Delivery, CRC Press,Inc., Boca Raton, Fla.). Units for unbound drug are given in moles perliter, and units for viscoelastic polymers are given in units ofequivalents per liter, which would describe any viscoelastic polymerwith any miotic or mydriatic drug.

In FIG. 2, curve A represents unbound drug, wherefor the initialconcentration of 0.0500 moles/liter is diminished to 0.0084 moles/literafter 6 hours of dilution in the eye, caused by the turnover rate ofaqueous humor.

Curve B of FIG. 2 represents a combination of unbound drug (noviscoelastic polymer present) and ion-complexed (bound)drug-viscoelastic polymer. In this curve, the viscoelastic polymer-drugcomplex has a predicted cooperative binding constant of 5×10⁻² (Hayakawaet al., 1983, Macromolecules 16:1642). This value was determined forcarboxymethylcellulose (as a model anionic viscoelastic polymer) with ahydrophilic cation of dodecyltrimethylammonium ion. From curve B it maybe seen that, with an initial concentration of unbound drug of 0.0500moles per liter, at 6 hours of aqueous humor turnover, 0.0340 moles perliter of medicament remains in the anterior chamber. This finalconcentration is more than 4-fold greater than the final concentrationof unbound drug observed after 6 hours.

Curve C of FIG. 2 represents ion-complexed (bound) drug-viscoelasticpolymer, wherein the initial concentration of 0.100 equivalents perliter (producing an equilibrium initial concentration of 0.500 moles perliter of unbound drug) is reduced to 0.0354 moles per liter after 6hours of duration in the eye, caused by the turnover of aqueous humor.This final concentration is more than 4 times greater than the finalconcentration of unbound drug, and slightly greater than that of CurveB. In this curve, the viscoelastic polymer-drug complex has a predictedcooperative binding constant of 5×10⁻² (Hayakawa et al., 1983,Macromolecules 16:1642).

Thus, from FIG. 2 it may be seen that two conditions of ion-complexedmiotic or mydriatic drug/polymer complex clearly demonstrate the effectof sustained release of drug with time, as compared to unbound drug, inthe anterior chamber of the eye.

In a third set of nonlimiting embodiments, the present inventionprovides for compositions which comprise microcapsules that are solubleor swellable in aqueous media and preferably biodegradable, whichthemselves comprise miotic or mydriatic agent, wherein the agent may beeluted with time as the microcapsule slowly dissolves, disintegrates, orswells. Typically, such microcapsules may desirably be smaller than thewavelength of light in order to prevent light scattering and impairedvision. In this procedure the agent of choice is incorporated into themicrocapsule during formation of the microcapsule. Since the viscosityof microcapsules is typically low, a viscoelastic polymer may be addedto maintain the anterior chamber.

Soluble microcapsules may be derived from inherently biodegradablepolymers, such as poly-DL-lactide or poly-DL-lactide-co-glycolide,which, in dry form, may be made into microcapsules containing anappropriate agent (Clarke et al., 1994, Polymer Preprints 35(2):73).Alternatively, soluble microcapsules may be derived from pH sensitivepolymers, where a change in pH can cause expansion of the microcapsule,leading to a sustained release drug delivery system. An example of sucha pH-sensitive polymer is poly(L)-lysine-alt-terephthalic acid, which,at pH values greater than 6, expands (Makino et al., 1994, PolymerPreprints 35: 54). Biodegradable microcapsules containing miotic ormydriatic agent may be prepared using polymers, such as polylactide orpolylactide-co-glycolide, that decompose after a period of time.

In a fourth set of nonlimiting embodiments, the present inventionprovides for compositions which comprise soluble copolymer micellescomprising a miotic or mydriatic agent, wherein the micelles comprise ahydrophilic and a hydrophobic portion, and the agent (in its unchargedform) is absorbed into the hydrophobic portion of the copolymer micelle(Arca et al., 1994, Polymer Preprints 35: 71). At equilibrium, ahydrophobic drug, such as phenylephrine, may be expected to reside bothinside and outside the copolymer micelle. When the preparation is placedin the anterior chamber of the eye, as the exterior agent is removed,the interior agent may be slowly released. Such copolymer micelles maypreferably be hydrophilic-hydrophobic orhydrophilic-hydrophobic-hydrophilic in character. Preferably, thehydrophilic blocks are derived from ethylene oxide and the hydrophobicblocks from propylene oxide (ethylene oxide-propylene oxide-ethyleneoxide block copolymers are sold under the trade names of Pluronic orPloxamer). Compositions comprising copolymer micelles may be mixed witha viscoelastic polymer, such as hydroxypropylmethylcellulose, in orderto maintain the structural integrity of the anterior chamber.

The present invention further provides for compositions comprising aplurality of miotic agents, or a plurality of mydriatic agents.

The amount of miotic or mydriatic agent present in the composition maybe that amount which produces the desired therapeutic effect; that is tosay, the desired pupil size for the desired period of time. Such amountswill vary between agents, but may readily be determined using thedose-response relationships known to the skilled artisan. Theconcentration of mitoic or mydriatic agent may vary from 0.001 mg/ml to20 mg/ml, and preferably from 0.025 mg/ml to 10 mg/ml. As one specific,nonlimiting example, where the miotic drug is acetylcholine chloride, apolymer/drug complex formulation may be prepared using a solution ofacetylcholine chloride with acetylcholine hyaluronate, where theacetylcholine concentration may be 10 mg/ml and the osmolality may beadjusted to 305 mosm/kg by mannitol. As another specific, nonlimitingexample, where the miotic agent is pilocarpine hydrochloride, apolymer/drug complex formulation may be prepared using a solution ofpilocarpine hydrochloride with pilocarpine hyaluronate, where thepilocarpine concentration may be 1 mg/ml and the osmolality may beadjusted to 305 mosm/kg by mannitol. As yet another specific,nonlimiting example, using the mydriatic drug atropine sulfate, asolution of atropine hyaluronate containing atropine sulfate may beprepared where the atropine concentration may be 0.3 mg/ml and theosmolality may be adjusted to 305 mosm/kg by mannitol. In each of theforegoing examples in this paragraph, the cationic drug may be mixedwith the polymer-drug complex in sterile water and the osmolality maythen be adjusted using the neutral agent mannitol.

Because it is important, during ophthalmologic surgery, to maintain theosmolality of the anterior chamber of the eye, the compositions of theinvention preferably exhibit an osmolality such that their introductioninto the eye may not detrimentally alter the osmolality of the anteriorchamber. The osmolality of the natural contents of the anterior chamberhas been reported to be 301-305 mosm/kg (Geigy Scientific Tables, Volume1, Ed. C. Lentner, Eighth Edition, 1981, Basle, Switzerland). Theosmolality of viscoelastic polymer drug ion complex could be maintainedby excess drug in its salt form (for example, a 3.0% solution ofphenylephrine chloride is isotonic in comparison to a 0.9 weight percentNaCl solution), or by a solution of, or in combination with, a neutralagent, such as glycerine (where a 2.6 weight percent solution isisotonic relative to a 0.9 weight percent NaCl solution) or mannitol(where a 5.07% solution is isotonic relative to a 0.9 weight percentNaCl solution). If traditional isotonic solutions are used, which maycontain sodium ions, potassium ions, calcium ions, etc., such ions mayprematurely displace the ion-complexed drug, releasing it into solution,and an excess of the cationic drug may be required to be added in orderto readjust the polymer-drug equilibrium. In preferred embodiments ofthe invention, the osmolality of the compositions may be between about280 and 340 mOsm/kg, and preferably between about 280-340 mOsm/kg.

In order to maintain the structural integrity of the anterior chamber ofthe eye, the compositions of the invention must be sufficiently viscoussuch as to prevent the chamber from collapsing during surgicalmanipulation. The compositions should also, however, be sufficientlyfluid to permit their introduction into the anterior chamber byinjection or extrusion, as well as their removal (for example, byirrigation) at the conclusion of the surgical procedure. Accordingly,the viscosity of a composition according to the invention is between1,000 and 60,000 centistokes and preferably between 2,500 and 40,000centistokes. Where viscoelastic polymers are used, the concentrations ofviscoelastic polymer are preferably between about 10 mg/ml and 30 mg/mlin aqueous (preferably isotonic) solution.

METHODS OF USING COMPOSITIONS OF THE INVENTION

The compositions of the invention are particularly useful when employedduring a variety of ophthalmological surgical procedures, such asprocedures desirably performed while the pupil is dilated, includingintracapsular and extracapsular surgery and fistulizing procedures, andprocedures desirably performed while the pupil is miotic, includinganterior segment surgery, such as surgical separation of vitreo/cornealadhesions, separation of iris/corneal adhesions, and the placement ofphakic refractive implants and secondary aphakic implants.

For example, and not by way of limitation, compositions comprising amydriatic agent, according to the invention, may be used in standardextracapsular cataract surgery carried out under topical or retrobulbaranesthesia. It should be noted that retrobulbar anesthesia tends to makethe iris somewhat more sensitive to dilating or constricting drops(Starling's Law). The mydriatic composition of the invention may then beinjected into the anterior chamber before and/or after an appropriatecapsulotomy. Irrigation, aspiration, expression, or phacoemulsificationof the cataract may then be performed. The implant may then be inserted,and residual mydriatic viscous material may be irrigated from the eye.In such procedures, the composition of the invention may aid theextraction of the lens and implant placement.

In another nonlimiting example, miotic compositions according to theinvention may be used in standard myopic refractive implant placementprocedures. After a paracentesis is carried out, the miotic compositionmay be injected into the anterior chamber. Then, an entrance incisionmay be made, the implant may be positioned, the wound may be sutured,and the viscous miotic composition may be irrigated from the eye.

The use of compositions of the invention offer a number of advantages.First, the present invention provides for a composition which maysimultaneously provide both mechanical and pharmaceutical activitiesuseful in ophthalmological surgery. Second, the compositions of theinvention may be used to satisfy a long-felt need for a means forproviding sustained release of miotic or mydriatic agents duringsurgery. Third, the compositions of the invention may prevent or reducea rise in intraocular pressure which may be associated with the use of aviscoelastic solution which does not comprise a miotic agent. Fourth,the use of compositions of the invention may be used to preventposterior or anterior synechias by keeping the pupil dilated during theimmediate postoperative phase.

Moreover, during conventional surgery, with loss of the chamber andhypotony there is loss of iris tone and function. Since the viscouscompositions of the invention maintain the chamber and some degree ofintraocular pressure, and are in contact with the iris for a prolongedperiod of time, a reservoir effect is established so that chambermaintenance, enhanced iris tone and response and drug delivery areconcurrently achieved. Further, particularly when miosis is desired, thelong term effect of miotics may blunt the pressure elevatory potentialof the viscoelastic.

Various publications are cited herein, which are hereby incorporated byreference in their entireties.

What is claimed is:
 1. A method of maintaining the structural integrityof the anterior chamber of the eye during surgery while concurrentlymaintaining the desired pupil size comprising administering acomposition comprising an acidic viscoelastic polymer and atherapeutically effective amount of a basic agent selected from thegroup consisting of miotic agents and mydriatic agents, to beadministered to a subject in need thereof.
 2. A method of maintainingthe structural integrity of the anterior chamber of the eye duringsurgery while concurrently maintaining the desired pupil size comprisingadministering a composition comprising an anionic viscoelastic polymerand a therapeutically effective amount of a cationic agent selected fromthe group consisting of miotic agents and mydriatic agents, to beadministered to a subject in need thereof.